Highlights from Recent Cancer Literature
Journal: Cancer Research (2019)

Shi and colleagues used quantitative mass spectrometry analysis to dissect the paracrine signaling between pancreatic cancer cells (PCC) and supporting stromal pancreatic stellate cells, two cell types that define the aggressive biology of pancreatic ductal adenocarcinoma (PDAC). They identified leukemia inhibitory factor (LIF) as secreted by the stromal cells and critical for PCC dedifferentiation and epithelial–mesenchymal transition. Antibody blockade of LIF or in vivo genetic deletion of the LIF receptor expressed on tumor-initiating cells negatively impacted tumor progression. The anti-LIF antibody augmented the efficacy of chemotherapy in mouse models of PDAC. Importantly, LIF levels correlated inversely with overall survival in human PDAC.Expert Commentary: This study exemplifies modulation of tumor cell behavior by surrounding stroma cells and provides a starting point for the investigation of tumor-stromal interactions that lead to malignant progression in PDAC, but also may mitigate the aggressiveness of the tumor. A major challenge that needs to be overcome, however, is the availability of tissue of sufficient quantity and quality to enable such genome-wide proteomic studies.Shi Y, Gao W, Lytle NK, Huang P, Yuan X, Dann AM, et al. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature 2019;569:131–5.While checkpoint blockade immunotherapy works by converting weak tumor-reactive T cells into cancer cell killers, underlying mechanisms remain elusive. Miller and colleagues compared exhausted CD8+ T cells from chronic viral infection and cancers to map gene expression and epigenetic landscapes in two distinct states of CD8+ T cells, progenitor and terminally exhausted cells. Only progenitors differentiated to terminally exhausted cells. Progenitors exhibited greater polyfunctionality in cytokine production and had enhanced proliferative capacity. Nevertheless, terminally exhausted cells retained the most potent cytotoxic activity. Importantly, progenitor cells were most responsive to anti-PD1 checkpoint blockade immunotherapy—proliferating and differentiating into terminally exhausted (yet cytotoxically functional) T cells that provided long-term control of cancers. In humans, correlation between higher ratios of progenitors with terminally exhausted CD8+ T cells may predict longer progression-free survival in response to anti-PD1 immunotherapy.Expert Commentary: T-cell exhaustion in cancer is heterogeneous. Particular subsets of exhausted cells respond to checkpoint blockade immunotherapy and may predict therapeutic response.Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol 2019;20:326–36.High-grade serous ovarian cancer (HGSC) is the most common type of gynecologic malignancy and has a poor prognosis. Eckert and colleagues carried out microdissection and proteomic analysis of stromal and epithelial compartments in matched preinvasive, primary, and secondary metastatic samples from patients with HGSC to identify candidate drivers of the disease. They found that nicotinamide N-methyltransferase (NNMT) was specifically upregulated in the stroma of metastatic lesions. NNMT was shown to be a master regulator of gene expression in cancer-associated fibroblasts through its ability to control histone methylation. NNMT was sufficient to drive cancer-associated fibroblast phenotypes that support HGSC growth and metastasis in mouse models. Furthermore, a small-molecule inhibitor of NNMT reduced tumor growth and increased stromal methylation in an orthotopic mouse model.Expert Commentary: This work supports the targeting of cancer-associated fibroblasts to normalize the metastatic stromal environment as an alternative approach to targeting metastatic disease.Eckert MA, Coscia F, Chryplewicz A, Chang JW, Hernandez KM, Pan S, et al. Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts. Nature; Published online May 1, 2019; doi: 10.1038/s41586-019-1173–8.Colorectal cancer is characterized by extensive molecular heterogeneity. To identify new biomarkers and drug targets, Vasaikar and colleagues isolated primary colorectal cancer tissue, normal adjacent colon, and matched blood from 110 patients. They performed a systematic analysis of the proteome, phosphoproteome, whole exome sequencing, transcriptome, and mutations. Proteomic analysis identified five distinct colorectal cancer subtypes, while transcriptome data identified four subtypes. Combining these classification systems yielded three unified multiomic subtypes: microsatellite instability (MSI), chromosomal instability (CIN), or mesenchymal enriched. Comparison of these colorectal cancer subtypes showed that MSI tumors had a significant abundance of glycolytic enzymes, as well as a decrease in TCA enzyme proteins. These results suggested a protein level adaptation that functioned to drive the Warburg effect in MSI colorectal cancers. They also observed a negative correlation between glycolytic activity and CD8 T-cell infiltration in the MSI subtype. These findings suggest combining glycolytic inhibitors with checkpoint inhibitors to treat MSI tumors.Expert Commentary: This comprehensive proteogenomic analysis identified numerous new potential biomarkers and therapeutic targets for colorectal cancer patients.Vasaikar S, Huang C, Wang X, Petyuk VA, Savage SR, Wen B, et al. Proteogenomic analysis of human colon cancer reveals new therapeutic opportunities. Cell 2019;177:1035–49.e19.Reprogramming of fatty acid metabolism is common in glioblastoma. Duman and colleagues showed that acetyl-CoA binding protein (ACBP) is essential for glioblastoma cell proliferation and reduced ACBP expression–induced senescence. Leveraging bovine shRNA variants deficient for long chain fatty acyl-CoA (LCACoA) binding, but not targeted by human ACBP shRNAs, they show that ACBP function in glioblastoma occurs through LCACoA binding and transport into the mitochondria. Medium chain fatty acids, which passively diffuse into the mitochondria, or acetone, which is readily converted to acetyl-CoA, rescued impaired proliferation from ACBP knockdown. Etomoxir, an irreversible inhibitor of carnitine palmitoyltransferase-1, was ineffective at rescuing proliferation in ACBP knockdown cells, confirming an essential role for transport of LCACoA in glioblastoma proliferation.Expert Commentary: Although metabolic reprogramming has been known for years as a hallmark of cancer, our understanding has been limited to the Warburg effect. This study shows how reprogramming of lipid metabolism may be exploited as a potential therapeutic strategy in glioblastoma.Duman C, Yaqubi K, Hoffmann A, Acikgoz AA, Korshunov A, Bendszus M, et al. Acyl-CoA-binding protein drives glioblastoma tumorigenesis by sustaining fatty acid oxidation. Cell Metabolism; Published online April 28, 2019; doi: 10.1016/j.cmet.2019.04.004.The complexity and heterogeneity of cerebellar cells have hindered studies on the origin and the development of brain tumors. Vladoiu and colleagues used single-cell transcriptomics to analyze more than 60,000 cells from the developing mouse cerebellum. They found that molecular subgroups of childhood cerebellar tumors reflected the transcription of cells from well-defined, temporally restricted cerebellar lineages. Sonic hedgehog medulloblastoma mirrored transcriptionally the granule cells. Group 3 medulloblastoma was similar to nestin-positive stem cells, while group 4 medulloblastoma resembled unipolar brush cells. In addition, the authors found that many tumors consisted of mixed populations of cells with different maturation. These data show that cerebellar tumors initiate during early brain development and thus explain why these malignancies peak during early childhood.Expert Commentary: This study shows that childhood brain tumors mirror conserved fetal transcriptional programs reflecting regional temporal and cellular origins in the developing brain.Vladoiu MC, El-Hamamy I, Donovan LK, Farooq H, Holgado BL, Sundaravadanam Y, et al. Childhood cerebellar tumours mirror conserved fetal transcriptional programs. Nature; Published online May 1, 2019; doi: 10.1038/s41586-019-1158–7.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.